P. gingivalis, a gram negative anaerobe identified as one of the putative oral bacteria associated with severe, chronic forms of periodontal disease, is a successful colonizer of oral tissues, and can invade and remain viable for extended periods in primary gingival epithelial cells (GECs). P. gingivalis is capable of intracellular replication and modulates many phenotypic and signaling properties of GECs. Unlike many intracellular pathogens that are harmful to their host, P. gingivalis does not induce apoptotic or necrotic death in GECs. Furthermore, P. gingivalis infection protects GECs against apoptosis induced by potent pro-apoptotic agents. However, the mechanisms of inhibition of GECs cell death-signaling pathway(s) and the key upstream mediators along with biochemical and morphological alterations induced by P. gingivalis have not been characterized. In addition, the consequences of prolonged invasion of GECs by the microorganism with respect to its increasing ability to multiply and disseminate the infection within epithelium, as well as the fate of infected cells remain to be determined. Overall goal of this project is to delineate the long-term outcomes of P. gingivalis infection on host cell status. Specifically, ultimate fate of infected cells will be investigated by examining cell death-survival markers and phenotypic events throughout the infection. Underlying mechanism(s) of the modulation of apoptotic cell responses mediated by P. gingivalis will be characterized and the microorganism's ability to multiply and spread within epithelium over time and its relation to host cell survival will be determined. Flow cytometry, fluorescence microscopy, phospho-specific Western blotting-activation assays, RNA interference, and microarray based approaches will be employed to achieve these goals. Periodontal diseases are among the most prevalent polymicrobial diseases affecting a majority of US population and impose a significant burden on the health care system. Moreover, oral infections associated with P. gingivalis have been linked as potential risk factors to major systemic health problems such as cardiovascular disease, diabetes mellitus, stroke and premature births. Investigations of proposed aims will contribute to the conceptual framework of the P. gingivalis interaction with host cells and define more targeted approaches to control P. gingivalis associated diseases.